This is an application for a Mentored Clinical Scientist Development Award for Dr. Laura Julian to develop a program of research evaluating neuroimaging correlates of depression and executive dysfunction (ED) in multiple sclerosis (MS). MS is the most common disabling neurological disease affecting young and middle aged adults;affecting approximately 350,000, people in the United States alone. Depression and cognitive impairment are the two most common neuropsychiatric symptoms in MS, each conferring significant disability. Among MS patients with depression, ED may be a clinical marker of a specific etiologically distinct subtype of depression that is (a) precipitated by neurodegenerative changes in fronto-subcortical brain regions, and (b) characterized by a poor or protracted course of depression. Evaluations of ED as a clinical marker have been conducted in other depressed populations, but this has not been investigated in MS. Preliminary evidence suggests that depression and ED predict underlying white matter lesion burden and a poorer course of depression in MS. The initial aims of this study are to evaluate depression and ED as predictors of underlying neuroimaging markers in MS. This investigation will confirm preliminary findings using traditional imaging techniques (T2-weighted MRI) to detect MS lesion volume. We will extend these findings to also explore changes in normal appearing white matter using a new imaging tool, diffusion tensor imaging. A second aim of this proposal is to evaluate ED and neuroimaging markers as predictors of the course of depression in MS over a period of 18 months. This reseach aims to identify a useful clinical marker that will identify patients with a specific subtype of depression. Identification of such markers holds promise in the future development of targeted therapies for specific subtypes of depression. This study is part of a larger mentored training program which includes structured mentorship, coursework, and other training activities to facilitate Dr. Julian's development as an independent clinical researcher.